1. Field of the Invention
The present invention relates to a method of increasing the absorption of a compound via the ocular, nasal, nasolacrimal or inhalation route into the circulatory system of a patient. In particular, a method comprising administering with the compound an absorption enhancers comprising a nontoxic, nonionic alkyl glycoside is provided. Additionally provided are methods of raising or lowering the blood glucose level by administering glucagon or insulin, respectively, with such absorption enhancers. Finally, compositions for raising or lowering the blood glucose level are provided.
2. Background Art
The revolution in biotechnology has impacted on the pharmaceutical industry and on the practice of medicine by making available a variety of previously known and newly discovered proteins, e.g., insulin, growth hormone, interferons; peptides, e.g., cyclosporine, enkephalins and other synthetic peptides; as well as macromolecules, e.g., heparin and derivatives; drugs which open up an entirely new dimension to the treatment of disease. A serious limitation to the development and use of such agents, however, is the ability to deliver them safely and efficiently to their therapeutic site of action (Lee, V. H. L. et at., in "Peptide and Protein Drug Delivery," V. H. L. Lee ed. Marcel Dekker, New York, pp. 1-56 (1991)). Because these drugs are usually available in only small amounts, are expensive and are biologically fragile--subject to denaturation and degradation--a rapid and efficient route of delivery is an important requirement for their successful use in therapy. Unfortunately, for the most part, the practical delivery of such agents has been limited to injectable routes such as intravenous, intramuscular and subcutaneous administration. Insulin is the classic example of such an agent whose obligatory use in insulin-dependent diabetes mellitus requires administration via injection. In the case of other established macromolecular drugs, such as heparin, the requirement for delivery by injection and the availability of alternative, but far from ideal agents, such as the oral anticoagulants, has restricted the use of the injectable agent to the clinic or hospital, thus denying its benefits to a large outpatient population. Although many attempts have been made to safely and efficiently administer insulin, heparin and other macromolecular drugs by non-injectable routes, none have proved successful, and it has become apparent that the success of such attempts depends on the discovery of a safe and efficient agent to enhance absorption of the macromolecules (see Lee et at.).
Buccal absorption of insulin is minimal in the absence of a surfactant agent, but it has been shown to be improved with penetration-enhancers such as glycocholate and Brij 35. However, the low bioavailabilty observed and the possible toxicity of the enhancing agents used previously have made this route impractical (Oh, C. K. et at, Meth. Find. Exp. Clin. Pharmacol., 12:205-212 (1990)). Similar findings have been reported for insulin absorption across the rectal mucosa (Rytting, J. H. et al., (V. H. L. Lee, ed.) Marcel Dekker, New York pp. 579-594 (1991)). However, it has recently been reported that dodecylmaltoside was effective in promoting the absorption of high molecular weight sugar compounds, such as dextrans, and other molecules, such as carboxyfluoroscein, across the rectal mucosa of rats without producing any apparent histological change to the tissue (Murakami, M. et al., Int. J. Pharm., 79:159-169 (1992)). Hovgaard et al., (J. Controlled Release, 19:99-108 (1992)) reported the use of high concentrations of dodecyl maltoside to increase the absorption of insulin across the rectal mucosa in rats. High concentrations were found to be necessary for rectal absorption (3.2%-12.8% dodecyl maltoside). It was concluded by Hovgaard et al. that rectal absorption enhancers function at least in part because they render the insulin-enhancer complex more resistant to enzymatic degradation by intestinal digestive enzymes. The use of dodecyl maltoside in the reported concentrations would be too irritating and toxic to the much more sensitive ocular and nasal mucosa and thus unsuitable for ocular and nasal absorption enhancers.
A synthetic analogue of calcitonin, a hypocalcemic peptide has been shown to be effectively absorbed percutaneously in the rat by applying it in transdermal dosage form as a gel containing a combination of bile salts and the alkyl glycosides octylglucoside or octylthioglucoside (Ogiso, T. et al., Chem. Pharm. Bull., 39:449-453 (1991)).
We had previously shown that systemic delivery of insulin via the ocular and nasal-lacrimal route in amounts sufficient to lower blood sugar in experimentally diabetic rats was made possible by including 1% saponin in the eye drops with the insulin (Pillion, D. J. et al., Invest. Ophthalmol. Vis. Sci., 32:3021-3027 (1991)). However, saponins, which have also been used by others to promote ocular absorption of insulin (Chiou, G. C. Y. et al., J. Pharm. Sci., 78:815-818 (1989); Chiou, C. Y. et al., J. Ocular Pharmacol. 5:81-91 (1989); U.S. Pat. No. 5,182,258 (Chiou et al.), are a large and complex class of compounds, derived from plants, which are difficult to prepare in pure form and have deleterious properties such as being irritants (Price, K. R. et al., CRC Crit. Rev. Food Sci. Nutr., 26:27-135 (1987)). Another surfactant, Tween 20, which has the same 12 carbon alkyl side chain as dodecylmaltoside, but which has a polyoxyethylene moiety in place of maltose, has been reported to be almost without effect in allowing absorption of insulin in rabbit eyes (Chiou, et al., J. Pharm. Sci.,) Furthermore, saponin, fusidic acid, EDTA, polyoxyethylene-9-lauryl ether, glycocholate, taurocholate, deoxycholate and decamethonium as ocular absorption enhancers have met with limited success in promoting the ocular absorption of insulin (Pillion et al., Chiou et al., (J. Pharm. Sci.), Chiou et al. (J. Ocular Pharmacol.) and Yamamoto et al., J. Pharmacol. Exptl. Ther., 249:249-255 (1989)), but the toxicity of these agents makes their therapeutic usage problematic.
Intranasal administration of insulin in the form of a nasal spray with bile salts or laureth-9 as absorption enhancers has been tested in clinical trials with normal and diabetic subjects, but also with only limited success (Moses, A. C. et al., Diabetes, 32:1040-1047 (1983); Gordon, G. S. et al., Proc. Natl. Acad. Sci. USA, 82:7419-7423 (1985); Salzmann, R. et al., New Engl. J. Med., 312:1078-1084 (1985)). The major limiting factors which have prevented the practical development of this route for general use is the low efficiency of absorption across the nasal mucosa and the local and systemic toxicity of the penetration-enhancing agents used (Moses et al., Gordon et al., Salzmann et al and Chadwick, U.S. et al., Gut, 17:10-17 (1976)). Aerosolized insulin has been absorbed via the respiratory route, but only at low efficiency, probably because no absorption enhancer was employed (Wigley, F. M. et al., Diabetes, 20:552-556 (1971).
Dodecylmaltoside and other alkyl glycosides can readily be obtained in pure form and have well defined, simple structures (Neugebauer, J., "A Guide to the Properties and Uses of Detergents in Biology and Biochemistry," Calbiochem Corporation (1988)). They are mild nonionic surfactants which have generally been shown to be nontoxic to several different cell types (DiCorleto, P. E. et al., J. Immunol., 143:3666-3672 (1989) and LeGrue, S. J. et al., J. Natl. Cancer Inst., 69:131-136 (1982)). Octylglucoside had no effect on the viability or morphology of monocytes or endothelial cells (DiCorleto et al.) and was non-cytolytic to intact mouse fibrosarcoma cells (LeGrue et al.) Orally administered alkyl glycosides, including octyl .beta.-D-glucoside and dodecyl .beta.-D-maltoside, have also been shown to be metabolized to nontoxic metabolites by cleavage to sugars and long chain alcohols which enter into the pathways of carbohydrate and lipid metabolism. It was suggested that these compounds would be suitable for use as food additives because of their lack of toxicity (Weber, N. et al., J. Nutr., 114:247-254 (1984)). In contrast, other agents which have been shown to enhance the systemic absorption of insulin, such as bile salts or laureth-9, are known to be irritating to mucosal surfaces and are not metabolized to simple products in the body (Moses et al., Gordon et al., and Salzmann et al.). In the case of bile salts, it is known that they are toxic to the gastrointestinal mucosa when administered orally and that they cause ultrastructural abnormalities of the nasal mucosa when used to administer insulin by this route (Moses et al., Gordon et al., and Chadwick et al.).
Thus, many attempts have been unsuccessfully made to obtain a suitable, effective absorption enhancer for drugs, and there is a great need for such an enhancer. The ideal absorption or penetration enhancer would preserve the biological activity of the protein or other drug and thus should be nonreactive and non-denaturing. It should enhance the passage of the drug through membrane barriers without damaging the structural integrity and biological functions of the membrane. Most importantly, both it and its metabolites should be nonirritating and nontoxic, both at the site of application, and also systemically, since it is likely that any enhancer of drug absorption will itself be absorbed and have to be metabolized and/or cleared from the body. Such an absorption enhancer is provided herein.